Derivatives of a-norprogesterone



United States Patent 2 Claims ABSTRACT OF THE DISCLOSURE A-A-norpregnadiene-2-one-20-ol and carboxylic acid ester derivativesthereof having progestational activity which can be used instead ofprogresterone, for example, in the treatment of habitual abortion.

This application is a division of our application Ser. No. 399,838,filed Sept. 28, 1964.

This invention relates to and has as its object the provision of newphysiologically active steroids, methods for their production and novelintermediates useful in said preparation.

More particularly, this invention relates to the provision of steroidsof the formulae (EH3 CH3 :0

and

wherein X is halogen (e.g., chloro, bromo, fluoro) and R is selectedfrom the group consisting of hydrogen and acyl.

The preferred acyl radicals are those of hydrocarbon carboxylic acids ofless than twelve carbon atoms, as exemplified by the lower alkanoicacids (e.'g., acetic, propionic butyric and tert-pentanoic acid), thelower alkenoic acids, the monocyclic aryl carboxylic acids (e.g. benzoicand toluic acids), the monocyclic aryl lower alkanoic acids (e.g.,phenacetic and ,B-phenylpropionic acid), the cycloalkane carboxylicacids and the cycloalkene carboxylic acids.

The compounds of this invention possess progestational activity and thusmay be employed instead of progesterone, for example, in the treatmentof habitual abortion for which purpose they can be administered in thesame manner as progesterone, for example, the dosage being adjusted forthe relative potency of the particular steroid.

The final products of the instant invention may be prepared by theprocesses of this invention which entails a number of steps beginningwith A-norprogesterone as starting material. The process of the instantinvention may be represented by the following equations wherein R and Xare as hereinbefore defined:

In the first step of the instant process, A-norprogesterone is enolacylated as by treatment with an acid anhydride, for example, aceticanhydride in the presence of a peracid, for example, perchloric acid, toyield the 17(20) -dehydro- ZO-acyloxy derivative (Compounds A), whichare new compounds of the instant invention.

Compounds A are then treated with a peracid, for example,m-chloroperbenzoic acid, to yield the 17-substituted A-norprogesterone(Compounds B), which are also new compounds of this invention.

Compounds B are then dehydrogenated as by treatment with adehydrogenating agent, for example, 2,3-dichloro-5,6-dicyanobenzoquinone to yield the d -A-norpregnadiene derivatives,(Compounds C), which are new compounds of this invention.

Compounds C are then treated with a peracid, such as m-chloroperbenzoicacid to yield the 6,7-oxido derivatives (Compounds D) which are also newcompounds of the instant invention.

Treatment of Compounds D with 1 mole equivalent of a hydrohalic acid,for example, hydrochloric acid or hydrobromic acid yields the6-halo-7-hydroxy-A -A-norpregnene derivatives (Compounds P), which arealso new compounds of the instant invention.

Alternatively, Compounds D may be treated with an excess of hydrohalicacid, e.g., hydrobromic or hydrochloric acid at an elevated temperature,to yield the 6- chloro-A -A-norpregnadiene derivative (Compounds E),which are also new compounds of the instant invention.

The invention may be illustrated "by the following examples:

EXAMPLE 1 A -A-norpregnadiene2-one-20-o1 acetate (I) An ice-coldsolution of 1.5 ml. of acetic anhydride containing three drops ofperchloric acid is added to a solution of 250 mg. of A-norprogesteronein 8 ml. of carbon tetrachloride and 20 ml. of benzene and left at roomtemperature for one day. The reaction mixture is poured into ice-waterand additional carbon tetrachloride is added. The organic layer isseparated and washed with a saturated sodium bicarbonate solution and 8%salt solution, dried over sodium sulfate, and evaporated to dryness togive a 280 mg. residue. Plate chromatography of the residue using silicagel as the adsorbent and chloroform containing 1% of methanol as thedeveloping solvent gives a major band at about Rf 0.4, which isdetectable by ultraviolet. Elution with ethyl acetate and evaporation todryness gives a 232 mg. residue. Crystallization of the residue fromether-hexane gives 21 mg. of A -A- norpregnadiene-Z-one-ZO-ol acetatehaving a melting point of 131132. Recrystallization from isopropyl ethergives the analytical sample having melting point 131-132; 115

125;. 5.75, 5.92, 6.17).; x33? 234 m (19,400); TBKCHSM 9.11 (s., 18Me);8.83 (s., 19Me); 821 (s., 21Me); 7.90 (s., 20-aeetate) and 4.27 (s.,3-H) Analysis.-Calcd for C H O (342.46): C, 77.15; H, 8.83. Found: C,77.20; H, 8.79.

EXAMPLE 2 A -A-norpregnene-2,20-dione-1711-01 (III) A mixture of 150 mg.of m-chloroperbenzoic acid and 225 mg. of A-A-norpregnadiene-2-one-ZO-ol acetate in 4 ml. of chloroform is stirredat room temperature for two hours. The chloroform solution is washedfive times with 5% sodium hydroxide solution, twice with 8% saltsolution, dried over sodium sulfate and evaporated to dryness to give agum. The gum is treated with a hot solution of 280 mg. of potassiumhydroxide in 5 ml. of methanol and stirred at room temperature forthirty-five minutes and diluted with water. The precipitate is collectedby filtration and washed with water and dried to give 100 mg. of A-A-norpregnene-2,20-dione-17a-ol having a melting point of 210-212. Theanalytical sample is prepared by recrystallization fromchloroform-ether, M.P. 233-234", [01.] +5 (EtOH);

$13,290, 5.87, 5.95, 6.1714; 35.3.2? 234 mu (15,800); 300 m (143);TSKCHW 9.24 (s., 18Mo), 8.82 (s., 19-Me), 5.7121) (s.,'21Me); 7.15 (s.,17-hydroxy) and 4.25 (s.,

Analysis.-Calcd for C H O (316.42): C, 75.91; H, 8.92. Found: C, 76.09;H, 8.74.

4 EXAMPLE 3 A -A-norpregnene-2,20-rlione-1754-01 acetate (11) A mixtureof 61 mg. of A -A-norpregnene-2,2O-dione- 17a-0l and 61 mg. ofp-toluenesulfonic acid monohydrate in 0.6 ml. of acetic anhydride and 3ml. of glacial acetic acid is left at room temperature for twenty-twohours, diluted with water and neutralized with potassium carbonate. Thereaction mixture is extracted three times with ether, and the combinedether extracts are washed with 8% salt solution, dried over sodiumsulfate and evaporated to dryness. Crystallization of the residue fromisopropyl ether gives 50 mg. of A -A-norpregnene-2,20-dione-1704-01acetate having a melting point of 182-184. The analytical sample isprepared by recrystallization from isopropyl ether, M.P. 186.5187.5, [a]47 (EtOH);

KBr

m 5.78, 5.85, 5.94 (411.), 6.17).; 8 5.23? 234 m (16,300), 292, 154);781mm 9.31 (s., 18-Me), 8.81 (s., 19-Me) 7.95, (s., 17-acetate), 7.90(s., 21Me) and 4.26 (s., 3-H) Analysis.-Calod for C H O (358.46): C,73.71; H, 8.44. Found: C, 73.75; H. 8.34.

EXAMPLE 4 A -A-norpregnene-2,20-dione-17a-ol acetate (II) A solution of0.033 ml. of perchloric acid in 3 ml. of acetic anhydride is added to astirred suspension of 4.79 g. of A -A-norpregnene-2,ZO-dione-17a-ol inml. of acetic anhydride. The reaction mixture is stirred, at roomtemperature for thirty minutes and then poured into ice water andstirred until the oil which separates initially, solidifies. Theprecipitate is collected by filtration, and dried to give 4.76 g. of A-A-norpregnene-2,20-dione- 1704-01 acetate, M.P. 186187.

EXAMPLE 5 A -A-norpregnadiene-2,2O-dione-17a-ol acetate (IV) Hydrogenchloride is bubbled into a solution of 1.40 g. of A-A-norpregnene-2,20-dione-17a-ol acetate and 1.0 g. of2,3-dichloro-5,-dicyanobenzoquinone in 30 ml. of dioxane for fiveminutes and the flask is left at room temperature overnight. Thehydroquinone is filtered and the filtrate is evaporated to dryness. Theresidue is treated with chloroform and additional hydroquinone isfiltered. The filtrate is diluted with additional chloroform to a totalvolume of 80 ml. and passed through a 40 g. neutral alumina (activity 1)column. The column is eluated with 420 ml. of chloroform, and the eluateis evaporated to give a 1.42 g. residue, which is refluxed in 30 ml. ofcollidine for seventy-five minutes, cooled to room temperature anddiluted with chloroform. The organic layer is washed with 2N-hydrochloric solution, saturated sodium bicarbonate solution and 8%salt solution, dried over sodium sulfate and evaporated to dryness.Plate chromatography of the residue using neutral alumina (activity V)as the adsorbent and chloroform containing 10% hexane as the developingsolvent gives a major band at about R 0.5, which is detectable byultraviolet. Elution with ethyl acetate gives a residue which iscrystallized from isopropyl ether to give 764 mg. of A-A-norpregnadiene- 2,20-dione-17u-ol acetate having a melting point of176. The analytical sample is prepared by recrystallization fromisopropyl ether, M.P. 178-179", [12] 45 (EtOH); 131 5.78, 5.87, 6.18 and6.35;; 52.32? 277111 1 (16,300); TS(CH3)4 9.31 (s., 18Me), 8.88 (s.,19Me), 7.94 (s., 17- acetate), 7.92 (s., 21Me), 4.25 (s., 3H), 3.83 (d,d,- cl lpjs, 9.5 e.p.s., 6-H), 3.46 (d, d, 2.3 c.p.s., 9.5 c.p.s.,

Analysis.Calcd for C H O (356.44): C, 74.13; H, 7.92. Found: C, 74.09;H, 7.83.

EXAMPLE 6 A -A-norpregnadiene-2,20-dione-1704-01 (V) A mixture of 500mg. of A -A-norpregnadiene-2,20-

Cli0no-17o4-Ol acetate in 30 ml. of methanol is treated with 3 ml. ofpotassium carbonate solution and stirred at room temperature foreighteen hours. The reaction mixture is diluted with Water and theprecipitate collected by filtration to give 303 mg. of A-A-norpregnadiene-2,20- dione 1771-01 having a melting point of 24l243.The analytical sample is prepared by recrystallization fromacetonitrile, M.P. 247-248", [DC]D32+4ZO (EtOH);

AKB:

2.91, 5.87, 5.99, 6.20 and 6.35; A523? 278 m (22,600); T589304 9.18 (s.,18-Me), 8.89 (s., l9-Me), 7.71 (s., 21Me), 7.12 (s., 17-hydroxy), 4.26(s., 3H); 3.83 (d, d, 1 c.p.s., 9.5 0.p.s., 6-H), 348 (d, d, 2 e.p s.,9.5 c.p.s. 7-H) Analysis.-Calc'd for C H O (314.41): C, 76.40; H, 8.34.Found: C, 76.23; H, 8.44.

EXAMPLE 7 6a,7a-oxido-A -A-norpregnene-2,20-dione-1711-01 acetate (VII)mm 5.78, 5.86, and 6.13 8553. 235 m (11,700); TSKCEHU 928 (s., 18-Me),8.88 (s., 19Me), 7.94 (s., 17-acetate), 7.88 (s., 21-Me), 6.61 (d, d 1c.p.s., 3.5 c.p.s.; 7H), 6.18 (d, 3.5 c.p.s. 6H), 3.78 (s., 3-H)Analysis.Calcd for C H O (372.44): C, 70.94; H, 7.58. Found: C, 70.97;H, 7.57.

EXAMPLE 8 6u,7 x-oxido-A -A-norpregnene-2,ZO-dione-17a-ol (VI) Followingthe procedure of Example 6, but employing 60,70t oxido-A-A-norpregnene-2,2O-dione-1711-01 acetate, there is obtained 6a,7a oxidoA -A-norpregnene 2,20- dione-l7ot-ol.

EXAMPLE 9 6,6-chloro-N-A-norpregnene-Z,20-dione-7a,17a-diol 17- Acetate(X) A solution of 61.5 mg. of 6a,7a-oxido-A-A-norpregnene-2,20-dione-17o-ol acetate in 6 ml. of chloroform istreated with a slight excess of hydrogen chloride in chloroform and leftat room temperature for two and one-half hours. The reaction mixture isdiluted with water and the layers separated. The aqueous phase isextracted with additional chloroform. The chloroform extracts are washedwith an 8% salt solution, dried over sodium sulfate and evaporated todryness. Crystallization of the residue from ethyl acetate-isopropylether gives 50 mg. of 6fi-chloro- A -A-norpregnene-2,20-dione-7a,17a-diol 17-acetate having a melting point of 236-238. Theanalytical sample is prepared by recrystallization from ethylacetate-isopropyl ether, M.P. 2465-2475", [0:] 76 (EtOH);

AKB:

m, 2.86, 5.85, and 6.1611; 85%? 235 (14,800);1 925 (s., 18-Me), 8.58(s., 19-Me), 7.94 (s., 17-aeetate), 7.90 (s., 21-Me), 5.93 (111., 7-H),5.20 (d, 2.5 5. 5.5. 6-H), 3.92 (s., 3-H) Analysis.-Calcd for C H O Cl(408.91): C, 64.60; H, 7.15. Found: C, 64.57; H, 7.16.

EXAMPLE 10 6-ch1oro-A -A-norpregnadiene-2,20-dione-1704-01 acetateHydrogen chloride is passed into a solution of 335 mg. of 61,718 oxido-A-A-norpregnene-2,ZO-dione-1712-01 acetate in 30 ml. of chloroform forthree minutes. The reaction mixture is left at room temperature for twohours, and then at 45 for one day. The reaction mixture is washed withwater, saturated sodium bicarbonate solution and 8% salt solution, driedover sodium sulfate and evaporated to dryness. Plate chromatography ofthe residue using neutral alumina (activity V) as the adsorbent andchloroform containing 20% hexane as the developing solvent gives a majorband at about Rf 0.8, which is detectable by ultraviolet. Elution withethyl acetate gives a residue which is crystallized from isopropylether-ethyl acetate to give 177 mg. of 6/3 chloro A-A-norpregnadiene-2,20- dione-17a-ol acetate having a melting point of183-184". The analytical sample is prepared by recrystallization fromisopropyl ether-ethyl acetate, M.P. 195.5-1965, 75 (EtOH);

555.. 5.78 (8b.), 5.87, 6.18 and 6.33m 8229.? 280 m (19,700); TSKCHHH9.26 (s., 18-Me), 8.84 (s., 19Me), 7.95 (s., 17a.ceta.te), 7.91 (s.,21-Me), 3.95 (s., 3-H), 3.78 (d, 2 e.p.s., 7H)

Analysis.Calcd for C H O Cl (390.89); C, 67.66; H, 6.96; Cl, 9.07.Found: C, 67.42; H, 7.00; CI, 9.09.

EXAMPLE 1 l 6-chloro-A -A-norpregnadiene-2,20-dione-1707-01 Followingthe procedure of Example 6, but employing 6-chloro-A-A-norpregnadiene-2,20-dione-1708-01 acetate, there is obtained 6chloro-A -A-norpregnadiene-2,20- dione-l7a-ol.

EXAMPLE 12 6fl-chloro-A -A-norpregnene-2,20-dione-7a- 17 a-dioldiacetateFollowing the procedure of Example 9, but substituting 6a,7a-oxido-A-A-norpregnene-2,20-dione-1771-01, there is obtained 65 chloro-A-A-norpregnene-2,20-dione-7a-17adiol.

EXAMPLE 13 6-bromo-A -A-norpregnadiene-2,20-dione-17u-ol acetate whereinR is selected from the group consisting of hydrogen and acyl derivedfrom a hydrocarbon carboxylic acid having less than twelve carbon atoms.

2. A -A-norpregnadiene-2-one-20-ol acetate.

References Cited UNITED STATES PATENTS 3,170,919 2/1965 Fried 260-5863,225,064 12/1965 Weisenborn 260-586 3,338,957 8/ 1967 Weisenborn260-488 LORRAINE A. WEINBERGER, Primary Examiner. VIVIAN GARNER,Assistant Examiner.

' US. 01. X.R.

